Abstract 1562: Correlative biomarker analysis of the phase II study of prexasertib, a cell cycle checkpoint kinase 1 (CHK1) inhibitor, in BRCA wild-type (BRCAwt), platinum-resistant recurrent, high-grade serous ovarian cancer (PR-HGSOC)
Authors: Elena Giudice, Grant Zurcher, Jayakumar Nair, Tzu-Ting Huang, Min-Jung Lee, Jane B. Trepel, Jung-Min Lee
Journal: Cancer Research (2023)

Abstract Background: High unmet needs exist to develop novel therapeutics and identify biomarkers to predict response in PR-HGSOC. We previously reported clinical activity of CHK1 inhibitor (CHK1i), prexasertib (a.k.a.ACR-368) in heavily pretreated BRCAwt PR-HGSOC (response rate [RR]: 30.7%, median progression free survival [PFS]: 5.8 [1.7-26.4] months; NCT02203513). Here, we aim to identify molecular correlates to CHK1i treatment. Methods: Prexasertib was given at 105 mg/m2 IV every 14 days in a 28-day cycle. Pre-treatment fresh core biopsies were collected from the biopsy cohort for RNA sequencing (RNAseq) and Whole Exome Sequencing (WES). Gene Set Enrichment Analysis (GSEA) and WES analysis were performed to identify molecular features that might predict response/resistance to CHK1i. Blood samples were collected at baseline and cycle 1 day 15 (C1D15) from both biopsy and non-biopsy cohorts. Multiparametric flow cytometry evaluating immune cell subsets was performed to identify changes in the immune response. Comparison of correlative markers was performed using a non-parametric Mann-Whitney test (GraphPad Prism, V9). Results: 49 BRCAwt PR-HGSOC patients (median 4 prior therapies [IQR 3-7]) were enrolled in both cohorts (biopsy cohort: n=25 and non-biopsy cohort: n=24) and received at least one dose of prexasertib. Among 39 RECIST evaluable patients, 18 had clinical benefit (CB), defined by PFS&amp;gt;6months. Tissue samples were obtained from 15 evaluable patients (biopsy cohort), and blood samples from 39 evaluable patients (both cohorts). While WES analysis did not reveal correlation between treatment response and genetic variants, GSEA showed insulin-like growth factor 1 (IGF1)/insulin pathway, nucleotide excision repair (NER), and homologous recombination (HR) pathways enriched in patients with no clinical benefit (NCB; PFS&amp;lt;6months). Upregulation of gene expression belonging to IGF1/insulin pathway was found in patients with NCB, i.e., IGF1R (p=0.02), IGF2BP3 (p=0.04), SLC2A4 (p=0.01), as well as genes belonging to the NER pathway, i.e., POLE (p=0.03) and RAD23A (p=0.02). Flow cytometry analysis showed an increase in the percentage of monocytic myeloid-derived suppressor cells (M-MDSCs) during CHK1i treatment in the NCB group (median 3.67% [0-15.9%] at baseline vs 7.8% [1.97-25.00%] at C1D15; p=0.009). Also, a higher percentage of M-MDSCs on C1D15 was found in NCB compared to the CB group (median 7.8% [1.97-25%] vs 5.52% [0.93-17.6%]; p=0.03). Conclusions: CHK1i yields promising clinical benefit in BRCAwt, PR-HGSOC, hard-to-treat population. Our preliminary biomarker analyses suggest that tumoral upregulation of IGF1/insulin and DNA repair pathways as well as a systemic increase of immunosuppressive cells, e.g., M-MDSCs may negatively impact CHK1i response. Citation Format: Elena Giudice, Grant Zurcher, Jayakumar Nair, Tzu-Ting Huang, Min-Jung Lee, Jane B. Trepel, Jung-Min Lee. Correlative biomarker analysis of the phase II study of prexasertib, a cell cycle checkpoint kinase 1 (CHK1) inhibitor, in BRCA wild-type (BRCAwt), platinum-resistant recurrent, high-grade serous ovarian cancer (PR-HGSOC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1562.